ICBDSR Report 2024

Italy Veneto, 2015 to 2018

total births in the 4-year period: 147,708 (livebirths: 147,318)
average births per year: 36,930 (livebirths: 36,830)
terminations of pregnancy legal in country: Yes
data include terminations of pregnancy: Yes
source structure: Population-based

A word from the program

NA

Selected data highlights

The following tables highlight selected sets of congenital anomalies, each with a specific focus.

Top Ten

Here are the program’s top ten conditions by frequency, selected among those with significant clinical and public health impact. These are the conditions that one is more likely to encounter in the population under surveillance and impact the largest number of individuals and their families.

Condition	Cases	Yearly Avg	Prevalence
Top 10 Conditions by Frequency
among specific diagnoses with major health impact, Italy Veneto, 2015-2018 shown are total cases for the reporting period, yearly average cases, and prevalence per 10,000
Down syndrome	484	121	32.8
Trisomy 18	91	23	6.2
Cleft palate without cleft lip	86	22	5.8
Renal agenesis	82	20	5.6
Cleft lip with or without cleft palate	77	19	5.2
Tetralogy of Fallot	69	17	4.7
Coarctation of aorta	68	17	4.6
Hydrocephaly	65	16	4.4
Spina bifida	59	15	4.0
Transposition of great vessels	52	13	3.5

Notable Seven

These conditions exemplify the impact of congenital anomalies on morbidity and mortality. For example, neural tube defects and critical congenital heart disease, when combined, account for approximately half of all infant deaths associated with congenital anomalies.

For several of these conditions, modifiable risk factors are well established, and primary prevention, if implemented appropriately, works. This implication is unpacked in a later section (‘what if scenario’).

	Yearly cases		Percent liveborn	Prevalence per 10,000
Seven highly impactful conditions
selected on the basis of high morbidity and mortality, and potential for primary prevention Italy Veneto, 2015-2018
	Program	Country	Percent liveborn	Prevalence per 10,000
Neural tube defects (NTD)
Neural tube defects, total	26	284	42	7.2
Spina bifida	15	158	53	4.0
Anencephaly	8	91	15	2.3
Orofacial
Cleft palate without cleft lip	22	229	98	5.8
Cleft lip with or without cleft palate	19	205	94	5.2
Heart
Tetralogy of Fallot	17	186	91	4.7
Transposition of great vessels	13	138	96	3.5
Hypoplastic left heart syndrome	5	51	53	1.3
Estimated from program prevalence extrapolated to total country births. Italy births for 2022 from World Bank

The full table

This more expansive set of major congenital anomalies, internal and external, includes most conditions of significant clinical and public health impact. A more detailed view of Trisomy 21 (Down syndrome) is included in a later section. Note: a child with multiple anomalies will be counted in all pertinent rows.

	All births			Livebirths
Selected congenital conditions by system
number of cases and prevalence (prev) per 10,000, for all births and livebirths Italy Veneto, 2015-2018
	Cases	Prev	95% CI	Cases	Prev	95% CI
Neural tube defects (NTD)
Neural tube defects, total	106	7.2	5.9 - 8.7	45	3.1	2.2 - 3.9
Spina bifida	59	4.0	3.0 - 5.2	31	2.1	1.4 - 2.8
Anencephaly	34	2.3	1.6 - 3.2	5	0.3	0.0 - 0.6
Encephalocele	13	0.9	0.5 - 1.5	9	0.6	0.2 - 1.0
Other brain
Hydrocephaly	65	4.4	3.4 - 5.6	30	2.0	1.3 - 2.8
Microcephaly	42	2.8	2.0 - 3.8	39	2.6	1.8 - 3.5
Holoprosencephaly	15	1.0	0.6 - 1.7	-	-	-
Eye and Ear
Microphthalmos	6	0.4	0.1 - 0.9	6	0.4	0.1 - 0.7
Microtia	4	0.3	0.1 - 0.7	4	0.3	0.1 - 0.7
Anophthalmos	1	0.1	0.0 - 0.4	1	0.1	0.0 - 0.4
Anotia	1	0.1	0.0 - 0.4	1	0.1	0.0 - 0.4
Orofacial
Cleft palate without cleft lip	86	5.8	4.7 - 7.2	84	5.7	4.5 - 6.9
Cleft lip with or without cleft palate	77	5.2	4.1 - 6.5	72	4.9	3.8 - 6.0
Choanal atresia bilateral	15	1.0	0.6 - 1.7	15	1.0	0.5 - 1.5
Heart
Tetralogy of Fallot	69	4.7	3.6 - 5.9	63	4.3	3.2 - 5.3
Coarctation of aorta	68	4.6	3.6 - 5.8	68	4.6	3.5 - 5.7
Transposition of great vessels	52	3.5	2.6 - 4.6	50	3.4	2.5 - 4.3
Hypoplastic left heart syndrome	19	1.3	0.8 - 2.0	10	0.7	0.3 - 1.1
Gastrointestinal
Small intestinal atresia/stenosis	48	3.2	2.4 - 4.3	47	3.2	2.3 - 4.1
Anorectal atresia/stenosis	5	0.3	0.1 - 0.8	5	0.3	0.0 - 0.6
Esophageal atresia	4	0.3	0.1 - 0.7	4	0.3	0.1 - 0.7
Genitourinary
Hypospadias	318	21.5	19.2 - 24.0	318	21.6	19.2 - 24.0
Renal agenesis	82	5.6	4.4 - 6.9	71	4.8	3.7 - 5.9
Undescended testis	54	3.7	2.7 - 4.8	54	3.7	2.7 - 4.6
Indeterminate sex	5	0.3	0.1 - 0.8	5	0.3	0.0 - 0.6
Epispadias	2	0.1	0.0 - 0.5	2	0.1	0.0 - 0.5
Bladder exstrophy	2	0.1	0.0 - 0.5	2	0.1	0.0 - 0.5
Cystic kidney	-	-	-	-	-	-
Limb
Limb deficiency (LD), total	41	2.8	2.0 - 3.8	35	2.4	1.6 - 3.2
LD transverse	18	1.2	0.7 - 1.9	16	1.1	0.6 - 1.6
LD unspec.	13	0.9	0.5 - 1.5	12	0.8	0.4 - 1.3
LD intercalary	5	0.3	0.1 - 0.8	5	0.3	0.0 - 0.6
LD postaxial	4	0.3	0.1 - 0.7	3	0.2	0.0 - 0.6
LD preaxial	2	0.1	0.0 - 0.5	1	0.1	0.0 - 0.4
LD axial	0	-	-	0	-	-
Polydactyly preaxial	-	-	-	-	-	-
LD mixed	-	-	-	-	-	-
Abdominal
Diaphragmatic hernia	21	1.4	0.9 - 2.2	17	1.2	0.6 - 1.7
Omphalocele	12	0.8	0.4 - 1.4	2	0.1	0.0 - 0.5
Gastroschisis	1	0.1	0.0 - 0.4	-	-	-
Prune belly sequence	1	0.1	0.0 - 0.4	1	0.1	0.0 - 0.4
Chromosomal
Down syndrome	484	32.8	29.9 - 35.8	190	12.9	11.1 - 14.7
Trisomy 18	91	6.2	5.0 - 7.6	18	1.2	0.7 - 1.8
Trisomy 13	42	2.8	2.0 - 3.8	5	0.3	0.0 - 0.6
Note a dash (-) indicates data not available or not provided

Program Comment

The program leads provide their insights on data, operations, and recent achievements. Their interpretation of the data is particularly valuable because of their local experience and knowledge.

TThe program is multi-source and population-based. It covers an area of 18,345 km2 and a population of nearly 4.9 million (2018 data).
The overall prevalence of congenital and chromosomal anomalies appears to be within the range of what is expected for programs with similar methodology.
During the reporting period, births overall have decreased from about 38 thousand (2015) to 32 thousand (2018). The program now integrates multiple data sources, including hospital discharge records (SD), the regional birth registry, and the regional rare disease registry, among others. The aim is to continously improve the completeness and accuracy of surveillance. Progress has also being made in improving the interoperability between different classification systems, including ORPHA codes, across the different data sources.

Down syndrome (trisomy 21)

By far the most common chromosomal anomaly, Down syndrome is known to occur more frequently (has a higher risk of occurrence) in births of women with higher maternal age

This pattern is universally observed, provided there is no significant bias toward missing pregnancies with Down syndrome in older women (e.g., because of unreported pregnancy terminations)

	All cases			Livebirths
Down syndrome, overall and by maternal age
separately for all births and livebirths, prevalence per 10,000 (Poisson exact confidence intervals) Italy Veneto, 2015-2018
	Cases	Prev	95% CI	Cases	Prev	95% CI
All maternal ages	484	32.8	29.9 - 35.8	190	12.9	11.1 - 14.7
< 20 years	2	13.6	1.7 - 49.2	1	6.8	0.2 - 37.9
20 to 24	9	7.8	3.6 - 14.8	5	4.3	0.5 - 8.1
25 to 29	20	6.1	3.7 - 9.5	15	4.6	2.3 - 6.9
30 to 34	88	17.5	14.1 - 21.6	40	8.0	5.5 - 10.4
35 to 39	189	48.7	42.0 - 56.2	61	15.7	11.8 - 19.7
40 to 44	152	126.3	107.0 - 148.0	47	39.0	27.9 - 50.2
45+ years	24	240.2	153.9 - 357.5	21	210.2	121.3 - 299.2
Age unspec.	-	-	-	-	-	-
Age unspec. = maternal age unknown or unspecified

Down syndrome - maternal age pyramid

Because of the relation between prevalence of Down syndrome and maternal age, the maternal age distribution in the population is a major determinant of the number of conceptions with Down syndrome in the population.

For programs that have maternal age specific data, one can compare the maternal-age ‘pyramid’ for all births in the population with that of births with Down syndrome. Typically, the distribution is skewed, with a relative excess of births with Down syndrome among the more advanced maternal age groups.

Down syndrome - birth rates matter

Despite the considerably higher risk (rates) of Down syndrome in mothers over 40 or 45 years, these age groups contribute comparatively fewer affected births than younger age groups. This is because birth rates matter: fewer births in the more advanced age groups mean fewer cases overall from those age groups.

A Pareto chart helps highlight the cumulative contribution of different age groups to the total number of cases. This information can help inform strategies for testing and counseling.

Linking risk factor profile and congenital anomalies

The term triple surveillance refers to a model of public health surveillance that births includes the full causal chain, from a) risk factors, which influence the number of affected pregnancies; to b) the affected pregnancies themselves, that are vulnerable to adverse health outcomes; and to c) the health outcomes in affected individuals. The burden of risk becomes expressed eventually in the burden of disease.

Historically, birth defect surveillance has focused on the second element, the occurrence of congenital anomalies.

However, improving outcomes (morbidity, mortality, disability) requires understanding and tracking risk factors (to improve primary prevention) and health outcomes (to improve care). Triple surveillance advocates integrating the tracking of all three elements in this causal chain. Together, these three domains provide clinicians, public health professionals, and policy makers with information to act.

To highlight such context, the next sections provide elements of country demographics, outcomes (mainly early mortality), and selected risk factors. These data, particularly those on risk factors and outcomes, are sometimes directly measured, and sometimes estimated. Birth defect programs with their partners can supplement these data with local assessments.

Country demographics

A surveillance program operates within its country’s demographic situation and trends. This information adds meaning and context to birth defect surveillance information.

Key Indicator	2022 data
Demographic Indicators, Italy
on population, births, life expectancy
Total population	58,940,425
Number of births	394,901
Birth rate (per 1000 pop)	6.7
Fertility (births per woman)	1.2
Life expectancy at birth (years)	82.9
Source: World Bank (accessed Sept 2024)

From program to country

Many (though not all) programs cover a proportion of the country in which they operate. In this setting, a common question is what the program can tell use about the impact of congenital anomalies country-wide, under the assumption that the program information is a good estimator for the country itself. This assumption, of course, needs to be carefully examined, and the program staff typically has the local knowledge to help frame such estimates within the strengths and limitations of the data.

The table below uses the prevalence measured within the program to estimate the number of births with selected congenital anomalies for the entire country. These extrapolations have limitations, and in most cases are illustrative. However, at times a program that covers a proportion of the population may be the only practical window into congenital anomalies country-wide.

	All cases	liveborn
A window into the country: Italy, 2022 estimates
Country-wide estimates for selected conditions (394,901 births), extrapolating from program data
Neural tube defects (NTD)
Neural tube defects, total	283	121
Spina bifida	158	83
Anencephaly	91	13
Encephalocele	35	24
Other brain
Hydrocephaly	174	80
Microcephaly	112	105
Holoprosencephaly	40	-
Eye and Ear
Microphthalmos	16	16
Microtia	11	11
Orofacial
Cleft palate without cleft lip	230	225
Cleft lip with or without cleft palate	206	193
Choanal atresia bilateral	40	40
Heart
Tetralogy of Fallot	184	169
Coarctation of aorta	182	182
Transposition of great vessels	139	134
Hypoplastic left heart syndrome	51	27
Gastrointestinal
Small intestinal atresia/stenosis	128	126
Anorectal atresia/stenosis	13	13
Esophageal atresia	11	11
Genitourinary
Hypospadias	850	852
Renal agenesis	219	190
Undescended testis	144	145
Indeterminate sex	13	13
Epispadias	5	5
Bladder exstrophy	5	5
Limb
Limb deficiency (LD), total	110	94
LD transverse	48	43
LD unspec.	35	32
LD intercalary	13	13
LD postaxial	11	8
LD preaxial	5	3
Abdominal
Diaphragmatic hernia	56	46
Omphalocele	32	5
Chromosomal
Down syndrome	1294	509
Trisomy 18	243	48
Trisomy 13	112	13
Note: includes conditions with at least 5 estimated cases. Assumes that prevalence estimates from program are valid country-wide.

Outcomes - early mortality

The relative impact of congenital anomalies on early mortality (neonatal, infant, and under 5 years) tends to increase as infant mortality due to other causes falls. This pattern has been observed worldwide. These general indicators of early mortality are tracked regularly by public health agencies.

Key Indicator	2022 data
Mortality Indicators, Italy
Neonatal mortality (per 1000)	1.6
Infant mortality (per 1000)	2.2
Under 5 mortality (per 1000)	2.6
Source: World Bank, accessed Sept 2024

Outcomes - mortality with congenital anomalies

A more specific indicator (infant deaths due to congenital anomalies) is more challenging to document accurately. Missed diagnoses, especially of internal anomalies, can lead to massive underestimates, especially in settings where diagnoses rely only or mostly on an external exam. The table below summarizes data and estimates from systematic public sources. However, local assessments from birth defect surveillance program can help improve the quality of this key indicator.

Age group	Percent	Deaths / 100k pop
Deaths due to birth defects, Italy
among infants (< 1 year old) and from first to fifth birthday
Infants	24.1	62.0
1 to < 5 yrs	13.4	1.5
Source: WHO mortality data 2020 (who.int)

Risk factors

Some modifiable exposures are well-established risk factors for congenital anomalies. Reducing these exposures is the basis for effective primary prevention. Here we focus specifically on smoking, diabetes, and folate insufficiency. These factors, both common and modifiable, increase the risk of major contributors to morbidity and mortality, including orofacial clefts, neural tube defects, and serious congenital heart disease. The impact of these risk factors depend on their frequency in the population. The following tables show frequency estimates for the country. In another section, these data are used to estimate the number of cases in the country potentially preventable by eliminating the risk factors.

Smoking

Smoking is associated with increased risk for many adverse pregnancy outcomes and several congenital anomalies, including orofacial clefts and probably congenital heart disease. The increased risk is relatively modest (odds ratios tipically less than 1.5) but the effect size, or number of cases due to smoking, depends on the rate of smoking among women who become pregnant. Here we used country-specific estimates of smoking in women of reproductive age (see table for references). Rates of smoking during pregnancy tend to be lower, but by the time many women know they are pregnant, the at-risk period for congenital anomalies has often already passed.

Women	Frequency (%)
Smoking in women
Frequency in two different groups, Italy
Of reproductive age	21.7 ( 18.3 - 25.1 )
During pregnancy	16.1 ( 11.0 - 21.9 )
Source: IHME \| www.healthdata.org \| and Lange 2018

Diabetes

Maternal pregestational diabetes is associated with increased risk for many serious congenital anomalies, including spina bifida, several critical congenital heart defects, and multiple congenital anomalies, among others. In some cases the relative risk (or odds ratio) can be quite high, above 4 or 5 in some cases. The effect size (number of cases due to diabetes) depends on the frequency of diabetes, which tipically increases with age.

Age Group	Percent
Diabetes in women
Frequency by age group, Italy
15 to 19	0.3
20 to 24	0.4
25 to 29	0.5
30 to 34	0.7
35 to 39	1.4
40 to 44	2.6
45 to 49	3.9
Source: IHME \| www.healthdata.org

Folate insufficiency

Folate insufficiency is associated with increased risk for neural tube defects and perhaps other congenital anomalies. On a population-basis, well-implemented folic acid fortification is estimated to decrease the prevalence of neural tube defects below 6 per 10,000 or perhaps even lower. Folic acid fortification is most effective when it is mandatory and universal, meaning that it involves foods commonly consumed by large parts of the population (e.g., wheat, maize, rice, depending on culture and geography).

Mandatory	Food vehicle	Year started
Folic acid fortification
Status of mandatory fortification in Italy
No	-	-
Source: FFI \| fortificationdata.org

What if - prevention scenarios

What follows is a tricky but important exercise. By combining information about risk factors and prevalence of congenital anomalies, one can attempt to estimate the number of cases attributable to risk factors. This is illustrated in the table below, which uses prevalence information from the program and risk factor information (e.g., diabetes frequency in women) from country data. These estimates also require knowing the relative risk of disease given the exposure. Here we use odds ratios derived from high quality studies and metanalyses. These data then are fed into the Miettinen estimator of attributable fraction to generate the scenarios that you in the table.

	Prevalence per 10,000	attributable cases			Risk factor parameters
Attributable cases for selected risk factors
yearly estimates in program and in country, and per million births Italy Veneto, 2015-2018
	Prevalence per 10,000	Program	Country	per 1M births	Risk factor parameters
Neural tube defects (NTD)
Neural tube defects, total	7.2	4	47	120	Presumed folate insufficiency, prevalence > 6
Orofacial
Cleft palate without cleft lip	5.8	1	10	26	smoking, freq: 21.7%, OR: 1.22
Cleft lip with or without cleft palate	5.2	1	14	36	smoking, freq: 21.7%, OR: 1.34
Heart
Tetralogy of Fallot	4.7	0	4	9	diabetes, freq: 0.5%, OR: 4.89
Transposition of great vessels	3.5	0	2	4	diabetes, freq: 0.5%, OR: 3.34
Hypoplastic left heart syndrome	1.3	0	1	2	diabetes, freq: 0.5%, OR: 4.58
Odds ratios from literature, exposure frequencies from country estimates (see methods for details). NTD estimates only where ETOPFA are included or not legally allowed. See text for details.

Arguably, these estimates are simplistic. For one, they assume accurate inputs. For neural tube defects, they assume accurate prevalence, including of stillbirths and pregnancy terminations. On the exposure side, e.g., for smoking and diabetes, they assume that the rates in women are accurate and reflect the true exposure rate in the periconceptional period (or at risk period). Moreover, the estimates are generated ‘one at the the time’ and do not account for multiple exposures (e.g., diabetes plus smoking) or interactions among multiple exposures. And so on. Nevertheless, even rough estimates provide an important message. Some instances, perhaps many, of major and even lethal congenital anomalies are preventable by reducing the burden of risk in populations and individuals. And in the examples provided (smoking and diabetes in particular), the benefits extend beyond the prevention of congenital anomalies to the prevention of many other health conditions, for the fetus as well as for the parents..